scholarly journals Study of fabomotizole belonging to p-glycoprotein substrates

2017 ◽  
Vol 25 (4) ◽  
pp. 538-550
Author(s):  
I. V. Chernykh ◽  
A. V. Shchulkin ◽  
E. N. Yakusheva ◽  
M. V. Gatsanoga ◽  
N. V Popova
Keyword(s):  
Neuroprotective Activity ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Test Substance ◽  
P Glycoprotein ◽  
Wide Range ◽  
Model Independent ◽  
Clinically Significant ◽  
Potential Substrate

P-glycoprotein (Pgp) is a membrane efflux protein transporter with numerous drug-substrates. In addition, a lot of drugs alter the activity of the transporter. It can lead to drug-drug interactions during polypharmacy. Fabomotizole (afobazol) is a Russian anxiolytic drug with neuroprotective activity, applied over a wide range of indications. The drug belongs to a potential substrate of Pgp according to its chemical structure. Aim. The aim of the study was to assess belonging of fabomotizole to Pgp substrates. Materials and Methods. The work was performed on 12 male Chinchilla rabbits. The belonging of fabomotizole to Pgp substrates was evaluated by comparing pharmacokinetic parameters of the test-substance after course administration of known transporter inducers and inhibitors – rifampicin and verapamil respectively. Fabomotizole was administered orally as a single dose of 3.8 mg/kg b.w. and blood was taken from the ear vein after 5, 10, 15, 20, 30, 60, 90, 120 and 240 min followed by it's pharmacokinetic analysis by HPLC. Pharmacokinetic parameters of fabomotizole were manually calculated by a model-independent method. The animals were then divided into 2 groups of 6 rabbits each: the 1st group received verapamil at a dose 20 mg/kg b.w. 3 times a day for 14 days, the 2nd – rifampicin in a similar course and dose. After the administration of Pgp modulators the pharmacokinetics of fabomotizole were re-analyzed. Results. It was found that only the absorption coefficient of fabomotizole in the rifampicin series was significantly reduced by 1.27 times as compared to the parameter of intact animals (90% CI 0.66-0.94, p=0.04322). However, this change was not clinically significant, because 90% CI overlapped the range of 0.80-1.25, noted by FDA. The remaining pharmacokinetic parameters of Pgp marker substrate were not significantly changed in any series. This is evidence that fabomotizole is not a Pgp substrate. The insignificant participation of Pgp in fabomotizole pharmacokinetics testifies that the drug can be administered together with drug-modulators of transporter activity without dose correction. Conclusion. In vivo experiment on Chinchilla rabbits showed that fabomotizole is not a substrate of P-glycoprotein.

scholarly journals Acceleration of hematopoietic reconstitution with a synthetic cytokine (SC-55494) after radiation-induced bone marrow aplasia

Blood ◽  
1996 ◽  
Vol 87 (2) ◽  
pp. 581-591 ◽  
Author(s):  
AM Farese ◽  
F Herodin ◽  
JP McKearn ◽  
C Baum ◽  
E Burton ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Platelet Recovery ◽  
Hematopoietic Reconstitution ◽  
Radiation Induced ◽  
Complete Blood Counts ◽  
60Co Gamma Radiation

The synthetic cytokine (Synthokine) SC-55494 is a high-affinity interleukin-3 (IL-3) receptor ligand that stimulates greater in vitro multilineage hematopoietic activity than native IL-3, while inducing no significant increase in inflammatory activity relative to native IL-3. The aim of this study was to investigate the in vivo hematopoietic response of rhesus monkeys receiving Synthokine after radiation-induced marrow aplasia. Administration schedule and dose of Synthokine were evaluated. All animals were total-body irradiated (TBI) with 700 cGy 60Co gamma radiation on day 0. Beginning on day 1, cohorts of animals (n = 5) received Synthokine subcutaneously (SC) twice daily with 25 micrograms/kg/d or 100 micrograms/kg/d for 23 days or 100 micrograms/kg/d for 14 days. Control animals (n = 9) received human serum albumin SC once daily at 15 micrograms/kg/d for 23 days. Complete blood counts were monitored for 60 days postirradiation and the durations of neutropenia (NEUT; absolute neutrophil count [ANC] 500/microL) and thrombocytopenia (THROM; platelet count 20,000/microL) were assessed. Synthokine significantly (P .05) reduced the duration of THROM versus the HSA-treated animals regardless of dose or protocol length. The most striking reduction was obtained in the animals receiving 100 micrograms/kg/d for 23 days (THROM = 3.5 v 12.5 days in HSA control animals). Although the duration of NEUT was not significantly altered, the depth of the nadir was significantly lessened in all animal cohorts treated with Synthokine regardless of dose versus schedule length. Bone marrow progenitor cell cultures indicated a beneficial effect of Synthokine on the recovery of granulocyte-macrophage colony-forming units that was significantly higher at day 24 post-TBI in both cohorts treated at 25 and 100 micrograms/kg/d for 23 days relative to the control animals. Plasma pharmacokinetic parameters were evaluated in both normal and irradiated animals. Pharmacokinetic analysis performed in irradiated animals after 1 week of treatment suggests an effect of repetitive Synthokine schedule and/or TBI on distribution and/or elimination of Synthokine. These data show that the Synthokine, SC55 94, administered therapeutically post-TBI, significantly enhanced platelet recovery and modulated neutrophil nadir and may be clinically useful in the treatment of the myeloablated host.

scholarly journals The LC-MS/MS-Based Measurement of Isopimaric Acid in Rat Plasma and Application of Pharmacokinetics

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Doudou Huang ◽  
Jiaxi Cheng ◽  
Junqin Mao ◽  
Senlin Ma ◽  
Zenan Du ◽  
...  
Keyword(s):  
Internal Standard ◽  
Rat Plasma ◽  
Absolute Bioavailability ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Isopimaric Acid ◽  
Clinical Utilization ◽  
Mechanistic Basis ◽  
Oral Doses

Isopimaric acid (IPA) exhibits a diverse array of pharmacological activities, having been shown to function as an antihypertensive, antitumor, antibacterial, and hypocholesterolemic agent. However, few studies of the pharmacokinetics of IPA have been performed to date, and such analyses are essential to explore the in vivo mechanisms governing the biological activity of this compound. As such, we herein designed a selective LC-MS approach capable of quantifying serum IPA levels in model rats using an Agilent HC-C18 column ( 250   mm × 4.6   mm , 5 μm) via isocratic elution with a mobile phase composed of methanol 0.5% formic acid (91 : 9, v/v) at a 1 mL/min flow rate. Ion monitoring at m/z 301.2 [M-H]- was used to quantify IPA levels in plasma samples from these rats, while internal standard (IS) levels were assessed at m/z 455.3 [M-H]-. After validation, this approach was employed to conduct a pharmacokinetic analysis of rats administered IPA via the oral (p.o. 50, 100, or 200 mg/kg) and intravenous (i.v. 5 mg/kg) routes. Analyses of noncompartmental pharmacokinetic parameters revealed that IPA underwent secondary absorption following oral administration to these animals, with the two tested oral doses (50 and 100 mg/kg) being associated with respective absolute bioavailability values of 11.9% and 17.5%. In summary, this study may provide a foundation for future efforts to explore the mechanistic basis for the pharmacological activity of IPA, offering insights to guide its subsequent clinical utilization.

Assessment of Pharmacokinetic Drug–Drug Interactions in Humans: In Vivo Probe Substrates for Drug Metabolism and Drug Transport Revisited

2019 ◽  
Vol 59 (1) ◽  
pp. 507-536 ◽  
Author(s):  
Uwe Fuhr ◽  
Chih-hsuan Hsin ◽  
Xia Li ◽  
Wafaâ Jabrane ◽  
Fritz Sörgel
Keyword(s):  
Drug Transport ◽  
Quantitative Prediction ◽  
Pharmacokinetic Parameters ◽  
Glycoprotein P ◽  
Therapeutic Drugs ◽  
P Glycoprotein ◽  
Clinical Drug ◽  
Pharmacokinetic Drug

Pharmacokinetic parameters of selective probe substrates are used to quantify the activity of an individual pharmacokinetic process (PKP) and the effect of perpetrator drugs thereon in clinical drug–drug interaction (DDI) studies. For instance, oral caffeine is used to quantify hepatic CYP1A2 activity, and oral dagibatran etexilate for intestinal P-glycoprotein (P-gp) activity. However, no probe substrate depends exclusively on the PKP it is meant to quantify. Lack of selectivity for a given enzyme/transporter and expression of the respective enzyme/transporter at several sites in the human body are the main challenges. Thus, a detailed understanding of the role of individual PKPs for the pharmacokinetics of any probe substrate is essential to allocate the effect of a perpetrator drug to a specific PKP; this is a prerequisite for reliably informed pharmacokinetic models that will allow for the quantitative prediction of perpetrator effects on therapeutic drugs, also in respective patient populations not included in DDI studies.

scholarly journals Pharmacodynamic Assessment of Clarithromycin in a Murine Model of Pneumococcal Pneumonia

2002 ◽  
Vol 46 (5) ◽  
pp. 1425-1434 ◽  
Author(s):  
Pamela R. Tessier ◽  
Myo-Kyoung Kim ◽  
Wen Zhou ◽  
Dawei Xuan ◽  
Chonghua Li ◽  
...  
Keyword(s):  
Murine Model ◽  
Close Correlation ◽  
Bacterial Density ◽  
Pharmacokinetic Analysis ◽  
Human Pharmacokinetics ◽  
Time Curve ◽  
Pharmacodynamic Profile ◽  
Wide Range ◽  
Immunocompetent Mice

ABSTRACT The pharmacodynamic profile of clarithromycin (CLR) was evaluated with a murine model of pneumonia. Eight Streptococcus pneumoniae isolates, including three macrolide-sensitive and five macrolide-resistant strains, were inoculated intratracheally into immunocompromised ICR mice as 108-CFU bacterial suspensions. Orally administered CLR daily doses ranging from 5 to 600 mg/kg of body weight were given over 5 days, during which animal survival was monitored. The bacterial density in lung tissues was examined after 24 h of CLR treatment and in control groups. Pharmacokinetic analysis of CLR in mice demonstrated that the regimen of 150 mg/kg twice a day was representative of human pharmacokinetics and was used to compare the efficacy of CLR against sensitive and resistant S. pneumoniae strains. Immunocompetent CBA/J mice were also infected and treated as described above and evaluated for bacterial density and survival to assess the effect of the presence of leukocytes. All three pharmacodynamic parameters, the duration (percent) of the time that serum CLR concentrations remain above the MIC (%T>MIC), the ratio of the area under the concentration-time curve from 0 to 24 h (AUC0-24) to the MIC, and the ratio of the maximum concentration of drug in serum to the MIC, were found to be closely correlated to CLR bacterial efficacy (P < 0.001). Furthermore, all parameters had close correlation to bacterial density (r 2 = 0.72 to 0.82), median survival (r 2 = 0.93 to 0.94), and total percent survival (r 2 = 0.91 to 0.92). These in vivo data suggest that the bacterial activity of CLR is closely correlated with all three parameters over a wide range of exposures and, as a consequence of parameter interdependency, AUC0-24/MIC is the most reasonable predictor of antibiotic efficacy. In this neutropenic pneumonia model, CLR was less efficacious against S. pneumoniae strains for which MICs were ≥4 μg/ml. However, the presence of leukocytes in the immunocompetent mice resulted in improved bactericidal activity, relative to that in the neutropenic animals, despite an MIC of 4 μg/ml.

scholarly journals EXTH-53. A BRAIN-PENETRANT MICROTUBULE-TARGETING AGENT THAT DISRUPTS HALLMARKS OF GLIOMA TUMORIGENESIS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii98-ii99
Author(s):  
Eric Horne ◽  
Juan J Vicente Ruiz ◽  
Patrick Cimino ◽  
Erik Jung ◽  
Cong Xu ◽  
...  
Keyword(s):  
Xenograft Model ◽  
Cancer Therapeutics ◽  
Pharmacokinetic Analysis ◽  
Enhanced Sensitivity ◽  
Microtubule Targeting Agents ◽  
Wide Range ◽  
In Vivo Testing ◽  
Anti Tumor Activity ◽  
The Brain

Abstract Most cancer therapeutics developed to date are excluded from the brain and are therefore ineffective in treating glioma, the most devastating type of brain cancer in adults. Microtubule targeting agents (MTAs) are indispensable medicines to treat a wide range of solid and hematopoietic tumors, and evidence suggests that glioma is sensitive to MTAs; but most MTAs do not cross the blood-brain-barrier. To address this limitation, we developed a brain-penetrant MTA, ST-401, that inhibited the growth of human glioma in culture at nanomolar concentrations. ST-401 bound to the colchicine site, inhibited tubulin assembly and reversibly reduced microtubule (MT) dynamics. Testing of ST-401 on the NCI 60 cancer cell panel indicated that its anti-tumor activity does not correlate with any of the compounds tested thus far through this platform but showed weak correlations for two MTA that work through distinct mechanisms: taxol (p=0.46) and vinblastine (p=0.34). Thus, ST-401 may kill cancer cells through a novel mechanism related to disruption of MT function. We discovered that ST-401 killed patient-derived (PD) glioma isolates in both mitosis and interphase, and inhibited the formation of tumor microtubes, MT-rich structures that connects glioma cells to a network that is resistant to standard therapies. Pharmacokinetic analysis of ST-401 in mice shows brain penetration reaching antitumor concentrations, and in vivo testing of ST-401 in a xenograft model demonstrated significant antitumor activity. In an immunocompetent mouse model of platelet-derived growth factor B-driven glioma, ST-401 significantly enhanced the therapeutic efficacies of standard care therapies temozolomide and radiation therapy. Our study identified novel aspects of glioma tumorigenesis that exhibit enhanced sensitivity to MTAs and shows that the brain-penetrant MTA, ST-401, represents a promising chemical scaffold to develop therapeutics for the treatment of patients diagnosed with glioma.

THU0452 ANTINOCICEPTIVE EFFECT OF Α-PHELLANDRENE IN CHRONIC PAIN: IN SILICO PHARMACOKINETIC, MOLECULAR DOCKING AND IN VIVO EVALUATION

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 463.1-463
Author(s):  
Y. M. S. Pires ◽  
M. C. Leal de Moura ◽  
W. Amorim Dias ◽  
V. D. Pimentel
Keyword(s):  
Chronic Pain ◽  
Molecular Docking ◽  
Side Effects ◽  
Essential Oil ◽  
Opioid Receptors ◽  
In Silico ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Opioid Agonist

Background:The pharmacological approaches of chronic pain are a challenge in the clinical context. Currently, only palliative treatments are performed. The α-phellandrene (α-phel) is a cyclic monoterpene found in essential oils of aromatic plants, which presents several biological activities, such as antinociceptive, antihyperalgesic and immunostimulant.1,2Objectives:This study aimed to investigate the action of α-phellandrene in chronic pain throughin silicoandin vivoapproaches, aiming to develop a new therapeutic option for painful conditions, reducing analgesic doses and side effects.Methods:The pharmacokinetic analysis of α-phel was performed by PreADMET online server. The software ACD/ChemSketch 14.0 was used to optimize the 3D structure of α-phel. Molecular docking was performed with the software AutoDock Tools 1.5.6 to evaluate the pharmacodynamics interactions of α-phel and opioid receptors.The mechanism of action of α-phel in chronic pain was analyzedin vivo. Ethics Committee of UFPI approved this project (protocol n° 305/17). Female Swiss mice (25-30 g) underwent partial sciatic nerve ligation surgery to induce neuropathy. The neuropathic mice (N=6) were pre-treated with Naloxone (2 mg/kg, i.p.) or Saline (10 mL/kg, p.o.). After 20 minutes, they were treated with α-phel (6,25 mg/kg, p.o.) or morphine (5 mg/kg, i.p.) and evaluated by Von Frey test.Results:The predicted pharmacokinetic parameters (Table 1) suggest good intestinal absorption and good permeability. Plasma protein binding is elevated, however, it is reversible and technological alternatives, such as carrier systems, can improve it. The α-phel does not inhibit CYP3A4, it indicates a minimal possibility of interactions with others drugs and adverse reactions.Table 1.Pharmacokinetic parameters of α-phelIDVALUEBBB7.17054Buffer_solubility_mg_L1227.08Caco223.4164CYP_2C19 and 2C9_inhibitionInhibitorCYP_2D6_inhibition_substrateNonCYP_3A4_inhibitionNonCYP_3A4_substrateWeaklyHIA100.00000MDCK267.707Pgp_inhibitionNonPlasma_Protein_Binding90.00000Pure_water_solubility141.466The structure of α-phel binding opioid receptors is shown in Figure 1. The lowest ligand-receptor binding energies were, respectively: -6.0 kca/mol, -6.6 kcal/mol and -7.4 kcal/mol for the interaction of α-phel with Mu, Kappa and Delta receptors. It indicates that α-phel has high affinity for all three opioid receptors, binding in a strong and stable way.Figure 1.Graphical 3D representation of the binding modes of α-phellandrene with opioid receptors: A - Mu; B - Kappa; C – DeltaThe analgesic potential of the substance was testedin vivoas well. It was observed that Naloxone, an opioid antagonist, significantly reversed the effect of α-phel, indicating that it displays antinociceptive and antihyperalgesic activity through opioid system.Conclusion:The monoterpene α-phel presents antinociceptive activity and reduces the sensitivity in chronic pain through the activation of opioid receptors.Thus,in vivoandin silicoresults indicate that α-phel is an analgesic opioid agonist. This work may guide further preclinical studies, since α-phel may be an important strategy to treat chronic pain, with fewer side effects, dependence and tolerance than conventional drugs.References:[1]Nascimento AF, Camara CA, Moraes MM, Ramos CS. Essential oil composition and acaricidal activity of Schinusterebinthifolius from Atlantic Forest of Pernambuco, Brazil against Tetranychusurticae. Natural product communications. 2012 Jan:7(1):129-132.[2]Piccinelli AC, Santos JA, Konkiewitz EC, et al. Antihyperalgesic and antidepressive actions of (R)-(+)-limonene, α-phellandrene, and essential oil from Schinusterebinthifolius fruits in a neuropathic pain model. Nutritional neuroscience. 2015 Jul 1;18(5):217-24.Disclosure of Interests: :None declared

scholarly journals Population Pharmacokinetic Analysis of Isoniazid, Acetylisoniazid, and Isonicotinic Acid in Healthy Volunteers

2015 ◽  
Vol 59 (11) ◽  
pp. 6791-6799 ◽  
Author(s):  
Kok-Yong Seng ◽  
Kim-Hor Hee ◽  
Gaik-Hong Soon ◽  
Nicholas Chew ◽  
Saye H. Khoo ◽  
...  
Keyword(s):  
Isonicotinic Acid ◽  
Compartment Model ◽  
Hepatic Function ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Mixed Effects Modeling ◽  
Two Compartment Model

ABSTRACTIn this study, we aimed to quantify the effects of theN-acetyltransferase 2 (NAT2) phenotype on isoniazid (INH) metabolismin vivoand identify other sources of pharmacokinetic variability following single-dose administration in healthy Asian adults. The concentrations of INH and its metabolites acetylisoniazid (AcINH) and isonicotinic acid (INA) in plasma were evaluated in 33 healthy Asians who were also given efavirenz and rifampin. The pharmacokinetics of INH, AcINH, and INA were analyzed using nonlinear mixed-effects modeling (NONMEM) to estimate the population pharmacokinetic parameters and evaluate the relationships between the parameters and the elimination status (fast, intermediate, and slow acetylators), demographic status, and measures of renal and hepatic function. A two-compartment model with first-order absorption best described the INH pharmacokinetics. AcINH and INA data were best described by a two- and a one-compartment model, respectively, linked to the INH model. In the final model for INH, the derived metabolic phenotypes for NAT2 were identified as a significant covariate in the INH clearance, reducing its interindividual variability from 86% to 14%. The INH clearance in fast eliminators was 1.9- and 7.7-fold higher than in intermediate and slow eliminators, respectively (65 versus 35 and 8 liters/h). Creatinine clearance was confirmed as a significant covariate for AcINH clearance. Simulations suggested that the current dosing guidelines (200 mg for 30 to 45 kg and 300 mg for >45 kg) may be suboptimal (3 mg/liter ≤Cmax≤ 6 mg/liter) irrespective of the acetylator class. The analysis established a model that adequately characterizes INH, AcINH, and INA pharmacokinetics in healthy Asians. Our results refine the NAT2 phenotype-based predictions of the pharmacokinetics for INH.

Model-Based Dose-Exposure-Response Assessment for Lead and Backup Spectinamide in a Mouse Model of Tuberculosis

2020 ◽  
Author(s):  
◽  
Santosh Wagh ◽  
Keyword(s):  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Response Relationship ◽  
Exposure Response ◽  
Antibiotic Effect ◽  
Post Antibiotic Effect

Despite decades of research, tuberculosis remains the oldest pathogen-based disease that is the leading cause of death from a single infectious agent. Among many anti-tubercular therapies under investigation, the semisynthetic compounds spectinamides are a promising novel class of anti-tuberculosis agents. One such lead candidate, spectinamide 1810, and backup spectinamide 1599 have demonstrated excellent efficacy, safety, and drug-like properties in various in vitro and in vivo assessments. The dose-ranging and dose fractionation studies were designed to characterize the dose-exposure-response relationship for lead and backup spectinamide in a mouse model of Mycobacterium tuberculosis infection. In this current study, we used 26 and 23 combinations of dose level and dosing frequency for the lead and backup spectinamide, respectively. The dedicated pharmacokinetic studies with a collection of series of blood samples were conducted in healthy animals. Population pharmacokinetic analysis was performed using non-linear mixed effect modeling to estimate pharmacokinetic parameters in healthy animals. The Bayesian principles were applied for reliable pharmacokinetic estimation in infected animals by using informed priors obtained from healthy animals. The individual pharmacokinetic parameters were obtained for infected animals through post-hoc estimation and subsequently used for pharmacokinetic/-pharmacodynamic (PK/PD) indices and mechanism-based PK/PD modeling. The obtained data on spectinamides’ plasma concentrations and counts of colony-forming units were analyzed using a PK/PD approach as well as classical anti-infective PK/PD indices. The population pharmacokinetic analysis results suggest that there is no difference in the pharmacokinetic parameters of lead and backup spectinamide in infected animals as compared to healthy animals. The PK/PD index analysis showed that the efficacy of spectinamide 1810 is largely driven by concentration (Cmax/MIC) and exposure (AUC/MIC) rather than a threshold minimum inhibitory level (T>MIC). Although similar results were obtained for spectinamide 1599 in previously performed in vitro experiments, in the present in vivo studies, spectinamide 1599 did not demonstrate the expected correlation between efficacy and PK/PD indices. Therefore, we could not identify major drivers for the efficacy of this compound. Additionally, a novel mechanism-based PK/PD model with consideration to post-antibiotic effect could adequately describe the exposure-response relationship for lead and backup spectinamide. This supports the idea that the in vitro observed post-antibiotic effect of these spectinamides can translate to the in vivo situation, as well. Altogether we suggest, the obtained results and pharmacometric model for the exposure-response relationship of lead and backup spectinamides provide a rational basis for dose selection for future efficacy studies of these compounds against Mycobacterium tuberculosis in mice and other animal species.

scholarly journals Late-Stage Copper-Catalyzed Radiofluorination of an Arylboronic Ester Derivative of Atorvastatin

Molecules ◽  
2019 ◽  
Vol 24 (23) ◽  
pp. 4210 ◽  
Author(s):  
Gonçalo S. Clemente ◽  
Tryfon Zarganes-Tzitzikas ◽  
Alexander Dömling ◽  
Philip H. Elsinga
Keyword(s):  
Small Molecules ◽  
Late Stage ◽  
Unmet Need ◽  
Emission Tomography ◽  
Complex Molecules ◽  
Ester Derivative ◽  
Positron Emission ◽  
Wide Range ◽  
Clinically Significant

There is an unmet need for late-stage 18F-fluorination strategies to label molecules with a wide range of relevant functionalities to medicinal chemistry, in particular (hetero)arenes, aiming to obtain unique in vivo information on the pharmacokinetics/pharmacodynamics (PK/PD) using positron emission tomography (PET). In the last few years, Cu-mediated oxidative radiofluorination of arylboronic esters/acids arose and has been successful in small molecules containing relatively simple (hetero)aromatic groups. However, this technique is sparsely used in the radiosynthesis of clinically significant molecules containing more complex backbones with several aromatic motifs. In this work, we add a new entry to this very limited database by presenting our recent results on the 18F-fluorination of an arylboronic ester derivative of atorvastatin. The moderate average conversion of [18F]F− (12%), in line with what has been reported for similarly complex molecules, stressed an overview through the literature to understand the radiolabeling variables and limitations preventing consistently higher yields. Nevertheless, the current disparity of procedures reported still hampers a consensual and conclusive output.

In Vitro and In Vivo Inhibition of P-Glycoprotein (ABCB1) by a Novel Non-Substrate Compound: HG-829

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3986-3986
Author(s):  
Gisela Caceres ◽  
Robert W Robey ◽  
Lubomir Sokol ◽  
Kathy Rocha McGraw ◽  
William J Fulp ◽  
...  
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Proliferation Assay ◽  
Hek 293 ◽  
P Glycoprotein ◽  
Wide Range ◽  
Xenograft Models ◽  
Substrate Inhibitor

Abstract Abstract 3986 Background: P-glycoprotein (P-gp or ABCB1) is a common cause of multidrug resistance (MDR) in cancer and leukemia that serves to extrude amphipathic drugs from the plasma membrane. P-gp is an ATP-binding cassette (ABC) transporter that exports a wide range of anti-neoplastics that are structurally or functionally unrelated. The vast majority of P-gp inhibitors tested clinically act as competitive export channel inhibitors to promote antineoplastic retention. We investigated the in vitro and in vivo effects of a novel substituted quinoline P-gp modulator, HG-829, in MDR cell lines and xenograft models. Methods: In vitro activity of HG-829 was evaluated in the K562-daunomycin-selected (K562-R) cell line and the ABCB1-transfected human embryonic kidney-293 cell line (HEK-293-B1) using a variety of P-gp substrates (daunomycin, doxorubicin, taxol, etoposide, vincristine) in a 72h MTT proliferation assay, and results compared to the effects of cyclosporine-A (CsA). Rhodamine 123 export and retention was assessed by flow cytometry. Flank injections of K562-R and parental K562-S cells in female SCID beige mice were performed for xenograft models. ANOVA and Turkey's multiple comparison tests were used to determine significant differences between groups in the proliferation assay and xenograft studies. Differences in rhodamine intracellular retention and efflux were assessed by Student's t-test. Results: Treatment with HG-829 at 0.5uM and 1uM completely reversed resistance to each of the antineoplastics studied in both the K562-R and HEK-293-B1 cell lines, but did not sensitize parental cells. HG-829 sensitized K562-R cells to daunomycin 57-fold and 97-fold at concentrations of 0.5uM and 1uM, respectively (p<0.01). Similarly, resistance to taxol (HG-829 0.5uM p<0.01 and 1uM, p<0.001), vincristine (p<0.01), and etoposide (p<0.05) were completely reversed. Comparable results were obtained with the HEK-293-B1 cell line in which HG-829 potentiated doxorubicin cytotoxicity 33- and 25-fold at concentrations 0.5uM (p<0.01) and 1uM (p<0.001), respectively. Compared to CsA, HG-829 was 3-fold more potent at equimolar concentrations. Functional studies showed that HG-829 (2.5uM) completely inhibited P-gp mediated rhodamine efflux in K562-R and the HEK transfected cells (p<0.05), but had no effect in parental cells. Pre-incubation followed by inhibitor removal showed that HG-829 inhibited rhodamine export as long as 24h (p<0.05), whereas equivalent concentration of CsA inhibited export for only 30 min. HG-829 showed no consistent effects on P-gp-ATPase activity in membrane preparations, whereas verapamil, a known P-gp substrate, displayed concentration-dependent stimulation. In mice bearing K562-R and parental xenografts, intraperitoneal administration of HG-829 significantly potentiated the antitumor activity of daunomyicin compared to vehicle without a significant increase in toxicity. Tumor volumes in HG-829 treated mice decreased to levels comparable to that of the K562-parental cohort (p<0.01 vs. vehicle). Conclusions: HG-829 is a potent non-substrate inhibitor of P-glycoprotein with a prolonged duration of action. Clinical testing of HG-829 is warranted. Disclosures: No relevant conflicts of interest to declare.

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